1. Field of the Invention
The present invention relates to a novel phenylalanine derivative, more particularly to a phenylalanine derivative having a proteinase inhibition activity or a pharmaceutically acceptable salt thereof. The present invention also relates to a proteinase inhibitor containing the same as the effective ingredient.
2. Description of the Related Art
Various proteases exist in the body, as is well known. For example, the serine proteases of kallikrein, trypsin, plasmin, urokinase, etc. are known.
Of these, kallikrein is widely distributed in the blood and in various viscera and glands, and normally exists as its precursor prekallikrein and is activated by Hagenman factor or other proteases. The normal actions of kallikrein in the body are (1) lowering of the blood pressure by kallikrein-kinin system, (2) activation of the fibrinolysis by the formation of plasmin from plasminogen, (3) contribution to intrinsic blood coagulation, (4) activation of the complementary systems, and (5) improvement of local circulation in the viscera or glands. On the other hand, abnormal activation of kallikrein, in local areas, is accompanied by activation of the coagulation and fibrinolysis and the resultant disorder of local circulation and disseminated intravascular coagulation, causing tissue obstruction. This is believed to be a cause of inflammation, ulcer, etc. and of induction of allergic reactions due to activation of the complementary system.
Therefore, strong inhibitors of kallikrein are useful for control of blood pressure, treatment of inflammation, acute pancreatitis and pancreatic necrosis, ulcer, and allergies and for immunoregulators.
Trypsin is inherently present in the pancreas as the trypsinogen, but alcohol, cholelith, injury, etc. lead to its activation in the pancreas, resulting self-digestion of the pancreas and clinical symptoms of pancreatitus. Further, when trypsin is injected retrogradly to the pancreas in rats, severe pancreatitis is observed. It has been confirmed that this is curable by a trypsin inhibitor.
Therefore, strong inhibitors of trypsin are useful for the clinical treatment of pancreatitis.
For some time, research has been underway to develop protease inhibitors having such action. Among the same, as a drug having pharmacological properties relatively resembling the present invention, there is known, as shown in Table 3, the protease inhibitor, aprotinin, which is polypeptides obtained from ox lungs. When aprotinin is administered to humans, it becomes itself an antigen and thus results in side effects such as allergic reactions. Further, it cannot be used over long periods or repeatedly. Further, in recent years, FUT-175 as shown in Table 3, which has become known as a broad protease inhibitor, has been used for the improvement of acute pancreatitis. The broad inhibition spectrum, the short half life in vivo, the large hypotensive action, and the small LD.sub.50 value mean that full supervision is required in clinical use, and this places a large burden on both the patient and the doctor. The present invention has as its object the development of a compound which sufficiently resolves the problems of the prior art, with high selective inhibition action, low molecular weight, long half life in vivo, and a large LD.sub.50 value and a protease inhibitor containing the same as the effective ingredient.